Obesity, hypertension and glucose tol- erance disorders have become a grow- ing concern in recent years. It is esti- mated that over 220 million people suffer from diabetes. It is a condition con- ducive to cardiovascular diseases, ne- phropathy, retinopathy and neuropathy but also to the development of many types of cancer. Insulin resistance and hyperinsulinemia lead to increased con- centration of insulin-like growth factors, activation of IGF-R receptors, activa- tion of PI3K and Ras-Raf pathways and result in increased cell division. The greatest risk is associated with devel- oping stomach, pancreatic, colorectal, esophageal and lung cancer as well as breast and cervical cancer. Numerous cohort studies have confirmed that dia- betic patients treated with metformin show a lower cancer morbidity and mortality rate. The dominant mechanism of action is activation of the AMP-acti- vated protein kinase (AMPK) pathway and inhibition of mTOR protein, the key protein to regulate cell growth, apoptosis, proliferation and protein syn- thesis. Many clinical trials are currently under way to investigate the effective- ness of metformin in the prevention and treatment of neoplasms.
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Keeyy wwoorrddss:: metformin, oncological treat- ment, diabetes, AMPK, mTOR.
The influence of metformin in the etiology of selected cancers
Monika Pawałowska1, Anna Markowska2
1Department of Oncology, Poznan University of Medical Sciences, Poznan, Poland
2Department of Perinatology and Gynecology, Poland University of Medical Sciences, Poznan, Poland
Introduction
According to data gathered by World Health Organization (WHO) from 2008, approximately 1.5 billion people aged 20 and older were overweight [BMI (body mass index) 25–29.9 kg/m2]; more than 200 million men and almost 300 mil- lion women were classified as obese (BMI > 30 kg/m2). Between 1980 and 2008 the number of obese people doubled. It is widely known that factors such as obesity, lack of physical activity, and high-carbohydrate diet are con- ducive to glucose tolerance disorder. According to WHO figures from 2011, over 220 million people are suffering from diabetes in the world. The Inter- national Diabetes Federation (IDF) estimates that by 2025 the number of peo- ple with impaired glucose tolerance will increase to 472 million (9% of the adult population), of whom around 40–50% will develop type 2 diabetes. Recent studies show that diabetes is conducive not only to cardiovascular diseases, nephropathy, retinopathy and neuropathy, but also to the development of many types of cancers [1–4]. Recent data have shown that metformin, a drug commonly used in diabetic patients, can significantly decrease the incident rate and death risk associated with malignant cancers. In this paper we would like to present the mechanism of metformin’s anticancer action and its role in selected malignancies.
Diabetes and cancer
Despite a tremendous body of research conducted in this field, there are still many aspects of the pathomechanism associating diabetes with can- cer development that remain unclear.
Intense protein synthesis and rapid cell division within cancerous tissue demand high energy consumption. Therefore the proliferating cells need to ensure themselves a constant delivery of the basic energy source that is glu- cose. In the case of hypoglycemia cancer cells rely on glycosylation to pro- duce ATP (the Warburg effect) [5]. Some authors have shown that hyper- glycemia is connected with increased risk of cancer. Park et al. [4] compared populations of patients with a fasting serum glucose level under 109 mg/dl and above 126 mg/dl and showed that the cancer-related mortality rate was 38% higher in the latter group. The highest mortality in that group was asso- ciated with gastric cancer (HR: 1.52; 95% CI: 1.25–1.84) and lung cancer (HR: 1.48; 95% CI: 1.18–1.87). Jee et al. came to similar conclusions [6]. In this Korean study a significant increase in mortality rate was found among peo- ple with the fasting serum glucose level over 140 mg/dl when compared with a group with the level under 90 mg/dl (HR: 1.29; 95% CI: 1.22–1.37 among men and HR: 1.23; 95% CI: 1.09–1.39 among women). In the male population the highest death rate was associated with esophageal (HR: 1.44; 95% CI:
1.08–1.93), liver (HR: 1.57; 95% CI: 1.40–1.76), pancreatic (HR: 1.91; 95% CI: 1.52–
2.41) and colorectal (HR: 1.31; 95% CI: 1.03–1.67) cancer. The highest death
rate among women suffering from diabetes with fasting blood glucose level in the morning over 140 mg/dl was asso- ciated with liver (HR: 1.33; CI: 1.01–1.81), lung (HR: 1.50; CI:
0.94–1.78), breast (HR: 1.24; CI: 0.65–1.92) and cervical (HR:
1.81; CI: 1.03–3.15) cancer; however, no such association was found for gastric and colorectal cancer.
On the other hand, in most cases normoglycemia allows for a concentration of glucose appropriate to meet the needs of cancerous cells [7]. A meta-analysis by Johnson and Bowk- er [8] assessed the benefits of an intensified glycemic con- trol in patients with type 2 diabetes in the context of de - velopment of neoplasms. In the conclusion of the large randomized study which included populations of many thou- sands of patients, the authors did not find any decrease in the risk of cancer mortality rates among patients with type 2 diabetes with normal blood glucose level and HbA1c. These results do not support the thesis that hyperglycemia is linked to increased carcinogenesis.
In an experimental model for the study of the influence of glucose concentration on tumor growth, Tannock and Kopelyan [9] found that higher glucose concentration increased the rate of cell division. However, at a glucose lev- el of 5 mmol/L the intensity of cell division plateaus and any further increase in concentration does not lead to an increased rate of cell division. This suggests that hyper- glycemia has no effect on cell proliferation.
Therefore, hyperinsulinemia rather than hyperglycemia seems to be the factor inducing intense cell proliferation.
Activation of insulin receptors and insulin-like growth fac- tor receptors (IGF-R) localized on the surface of cancer cells leads to cell proliferation [10]. Insulin resistance and hyper- insulinemia lead to increased concentration of insulin-like growth factors, activation of IGF-R receptors and activation of PI3K and Ras-Raf pathways, and result in increased cell division.
Metformin – anticancer drug?
Metformin has been successfully used for many years to treat patients with type 2 diabetes. A multicentre, random- ized study conducted by UKPDS (United Kingdom Prospec- tive Diabetes Study) [11] in patients with type 2 diabetes showed that treatment with metformin reduced the risk of myocardial infarction and diabetes-related death by 30% as compared with treatment with insulin and sulphonylurea derivatives. Numerous cohort studies have confirmed the the- sis that patients with diabetes treated with metformin also have a lower risk of cancer incidence and mortality [12, 13].
Evans et al. [12] found a 23% reduction in cancer incidence among patients treated with metformin as compared with sulphonylurea derivatives. Another Canadian study [14]
during a five-year follow-up of 10 309 people with diagnosed type 2 diabetes showed a significant cancer-related mortality reduction among patients receiving metformin in compar- ison to patients treated with oral sulphonylurea derivatives or insulin (3.5% vs. 4.9% vs. 5.8%). A Scottish cohort study [13] conducted among 12 255 people suffering from type 2 diabetes showed a 7.3% rate of newly diagnosed cancer among patients treated with metformin as compared with
11.6% of patients treated with other drugs. The median time between the diagnoses of diabetes and cancer was 3.5 and 2.6 years respectively (p = 0.001). Decensi et al. [15] found in turn in their meta-analysis a 31% reduction of cancer inci- dence and mortality in diabetic patients taking metformin.
Metformin belongs to the biguanide class derived from goat’s rue (Galega officinalis), a herbaceous plant used in Ancient Egypt and medieval Europe [16–18]. It was first syn- thesized in 1922 by two scientists, Werner and Bellow from Trinity College, Dublin. The first biguanides (metformin and phenformin) were introduced in France in the 1950s after numerous publications by Jeane Sterne. They were withdrawn from the market after several years due to their severe adverse effects (phenformin) with particular focus on an increased risk of lactic acidosis. Having scored highly in many drug safety clinical trials, metformin (1,1-dimethylbiguanide) was introduced to the U.S. market in 1995 and gained more popularity with every year. The most common adverse effects after regular use of this drug are associated with the gas- trointestinal tract, e.g. nausea, flatulence, vomiting, diarrhea.
A small percentage of patients experience hives or other skin lesions. Lactic acidosis is very uncommon and affects mostly elderly people who suffer from circulation, liver or kidney failure. Apart from diabetics, metformin has also been successfully used in women with polycystic ovary syndrome, increasing the ovulation rate, and improving glucose tol- erance and disordered lipid balance [19–21].
The hypoglycemic effect of metformin relies on the direct inhibition of gluconeogenesis and glycogenolysis in the liv- er. Metformin increases anaerobic glycolysis of peripheral tissue, particularly in skeletal muscles. Furthermore, it has an ability to enhance the number of GLUT4 glucose trans- porters and insulin receptors.
Metformin’s mechanism of action is complex and may involve several pathways. The processes influenced by this drug include the following:
• activation of LKB1 (liver kinase B1)/AMPK (AMP-activated protein kinase) pathway,
• inhibition of cell division and/or promotion of apoptosis,
• promotion of autophagy,
• down-regulation of circulating insulin,
• activation of the immune system.
It is recognized that the basic mechanism of metformin action involves AMP-activated serine/threonine kinase, a type of protein that plays a key role in the regulation of cellular metabolism of both normal and cancer cells. AMP- activated protein kinase becomes activated under conditions of cellular energy deficit and a low AMP:ATP ratio. This resets the metabolic pathways from anabolic toward catabolic processes [22] and to promotion of e.g. glycolysis and oxi- dation of fatty acids; at the same time pathways of gluco- neogenesis, protein, cholesterol and fatty acid synthesis are stopped [23]. AMP-activated protein kinase activation by met- formin is mediated by LKB1 [24]. Liver kinase B1 is a sup- pressor protein. Its mutation is found in the hereditary Peutz- Jeghers syndrome characterized by the development of many hamartomatous polyps, skin lesions in the form of lentig- ines and a tendency to develop multiple carcinomas, par- ticularly of the small intestine, stomach, pancreas and colon.
The activation of AMPK by LKB1 leads to phosphoryla- tion of tuberous sclerosis complex 2 (TSC-2), which in turn inhibits the mTOR protein (mammalian target of rapamycin), a key protein which regulates processes of cell growth and angiogenesis, and promotes cell division and protein syn- thesis. The inhibiting effect of AMPK on mTOR results in blocking of the PI3K/PKB/Akt pathway, thus downregulat- ing the synthesis of many proteins, e.g. eukaryotic initia- tion factor 4e-binding protein-4E-SPs, ribosomal protein S6 kinase, responsible for mitotic promotion [25, 26] (Fig. 1). Met- formin may also inhibit mTOR dependent pathways in the absence of AMPK, LKB1 and TSC2 in a Rag GTPase depen- dent manner [27]. AMP-activated protein kinase also pro- motes cellular autophagy through the phosphorylation of cyclin-dependent kinase inhibitor protein, p27 [28].
The role of metformin in oncology
As mentioned, metformin significantly lowers the death risk associated with malignant cancers. If we look closer at the figures from the numerous studies [15, 29, 30] we will see that this phenomenon applies only to some types of cancer, e.g. esophageal, liver, colorectal, pancreas, breast and lung. In a Taiwanese study, Lee et al. [29] found a sub- stantial reduction in liver and colorectal cancer morbidity among patients taking metformin (HR: 0.58 and 0.38, respectively).
Breast cancer
Obesity and diabetes are acknowledged risk factors of breast cancer for peri- and postmenopausal women.
According to Thor and Anderson [31] the risk increases by 20% and the cancers very often are estrogen receptor pos- itive.
Many studies conducted on breast cancer lines have shown positive action of metformin on these malignant cells.
Alimova et al. [33] studied in diverse subtypes of breast can- cer cell lines the effect of metformin on receptor expression and molecular pathways that participate in cell prolifera- tion and apoptosis. Metformin inhibited cell proliferation by blocking the cell cycle at the G1 checkpoint, and downreg- ulated cyclin D1 and transcription factor E2F1 expression, with no impact on other cell cycle regulators, such as p27kip1 or p21WAF1. It has been proven that metformin inhibits the MAPK (mitogen activated protein kinase) signaling pathway as well as Act activity [34]. Another mode of metformin activ- ity is suppressing the phosphorylation of signal transduc- er and activator of transcription Stat3, also responsible for cellular proliferation and apoptosis, angiogenesis and acti- vation of expression of genes related to breast cancer sur- vival [31]. The cytotoxic effect of metformin on breast can- cer cells may also take place via damage to the poly(ADP-ribose) polymerases (PARPs) – enzymes respon- sible for genome integrity – and via activation of caspase associated with cell apoptosis [31, 35]. High and low-con- centration metformin in in vitro studies inhibited erbB2 expression and showed biological activity against estrogen receptors (ER) [30]. According to Liu et al. [36] metformin in vitro and in vivo (nude mice strain) exerts an inhibiting effect
in cell culture conditions and reduces tumor mass in ani- mal models. Bernstein et al. [37] tested receptor status in carcinoma cells after previous surgery in 90 female patients with diabetes, treated with metformin and other antidia- betic medication. In their work they noted that the frequency of progesterone-positive receptors in women treated with metformin was significantly higher in comparison to the group treated with other medication and these results may be used in breast cancer therapy.
Scientists from Texas [32] analyzed responses to neoad- juvant chemotherapy for early-stage breast cancer in 2529 women over a 17-year period – 2374 women were nondia- betic, 68 diabetic using metformin and 87 diabetic using oth- er treatment – and reported a complete pathological remission in 24% of women taking metformin versus 8%
of women taking other antidiabetic medication and 16% of nondiabetic patients (p = 0.02). More randomized studies are necessary to ascertain whether metformin improves responses to chemotherapy in women suffering from breast cancer and whether there is a benefit of adding this drug to conventional treatment [38, 39].
receptor
protein synthesis cell proliferation
and growth
FFiigg.. 11.. The role of metformin in the etiology of cancer. Adapted from: Cancer Res 2007; 67: 10804-10812 [25] – reprinted with permission
PTEN – phosphatase and tensin homologue deleted on chromosome 10;
PI3K – phosphatidylinositol-3-kinase; PKB/AKT – protein kinase B/Akt; mTOR – mammalian target of rapamycin; TSC-2 – tuberous sclerosis complex 2;
LKB1 – liver kinase B1; AMPK – AMP-activated protein kinase; 4E-BP1 – eukaryotic initiation factor 4E-binding protein; S6K – protein S6 kinases
AMPK LKB1 insulin
PI3K
PKB/AKT
TSC2
mTOR
4E-BP1 S6K
PTEN
metformin
Ongoing phase II and III clinical trials evaluate its role in breast cancer, where mTOR is suggested to be the shield [40].
During the recent ASCO (American Society of Clinical Oncology) meeting (2011) it was reported that the Clinical Trials Group from the National Cancer Institute of Canada has initiated enrollment of over 3500 women with node- positive and node-negative breast cancer who will receive metformin compared with placebo for 5 years [41].
Colorectal cancer
Colorectal cancer risk is higher in obese patients with type 2 diabetes. Patients treated with insulin are twice as like- ly to develop this type of cancer as compared to patients taking metformin [42]. It has been supported that aberrant crypt foci (crypts of Lieberkuhn) may play a role in colon can- cer pathogenesis [43].
The inhibiting effect of metformin on intestinal epithe- lial cell proliferation and the development of aberrant crypt foci and polyps has been shown in an animal model.
The mechanism of metformin-mediated suppression of the abovementioned precancerous states occurred via the
most common way – through AMPK activation and mTOR inhibition [43].
Studies of colon cancer cell lines prove that AMPK acti- vation is accompanied by lower expression of VEGF as well as GLUT1 and COX-2 glucose transporter, which may addi- tionally result in cell apoptosis [46]. Other studies have shown that metformin also induces apoptosis in suppressor p53-deficient colon cancer cells [47].
The findings of these studies show that type 2 diabetic patients constitute a high risk group for colon cancer and suggest a preventive effect of metformin.
Pancreatic cancer
Jee et al. [6] estimated whether the increase in risk of death from pancreatic cancer depended on duration of diabetes. The scientists found that the mortality risk increased according to diabetes duration with a twofold rise in mortality for diabetes duration of less than 5 years and a threefold rise for diabetes duration of more than 10 years.
The evidence provided by an American study [48] explor- ing the relationship between metformin and pancreatic can- cer risk proved the protective effect of the drug. According to the authors it reduces the risk of pancreatic cancer by over a half (HR: 0.38, 95% CI: 0.22–0.69; p = 0.001).
Other cancers
In breast and endometrial cancer alike, the presence of progesterone receptors (PR) plays a vital role. A study by Cui et al. [49] established a significant IGF1-induced reduc- tion in the number of PR in breast cancer cells. This phe- nomenon has been linked with the activity of the PI3K/Akt/mTOR pathway and inhibition of PR gene tran- scription. Similar results were obtained by Xiu et al. [50] in an examination of endometrial cancer cell lines. The results of their study show that IGF2 mediates activation of the PI3K/Akt/mTOR pathway, 4E-BP and p70S6K phos- phorylation and a significant increase in cell proliferation, while both IGF1 and IGF2 inhibit expression of the PR A/B gene (Fig. 2). The authors also demonstrated that metformin exerts a counteracting effect on the abovementioned processes and this may imply that introduction of this drug combined with progesterone supplementation would result in a better response to treatment.
Ongoing clinical trials
The promising results of many cohort and experimen- tal studies triggered further clinical trials which aim to deter- mine whether this inexpensive, generally available and safe medication can reduce cancer incidence or improve cancer prognosis. Another interesting issue demanding further stud- ies is the aspect of metformin use in nondiabetic patients.
Could this group also benefit from metformin treatment?
Currently many phase I, II and III trials are under way to study metformin’s effect on breast, prostate, endometrial and pan- creatic cancer (Table 1). Perhaps in the near future met- formin’s antineoplastic activity will be generally recognized and eventually it will be applied in oncotherapy.
FFiigg.. 22.. The effect of metformin on PR expression. Adapted from:
J Steroid Biochem Mol Biol 2011; 126: 113-120 [50] – reprinted with permission
IGF-2 – insulin-like growth factor 2; IGR-1R – insulin-like growth factor receptor 1;
PTEN – phosphatase and tensin homologue deleted on chromosome 10;
PI3K/AKT – phosphatidylinositol-3-kinase/Akt; mTOR
– mammalian target of rapamycin; AMPK – AMP-activated protein kinase;
LKB1 – liver kinase B1; 4E-BP1 – eukaryotic initiation factor 4E-binding protein;
p70S6K – 70 protein S6 kinases; mRNA PR – progesterone receptor mRNA IGF-2
IGF-1R
PI3/AKT
4E-BP1/p70S6K
mRNA PR
Metformin
mTOR AMPK
LKB1
TTaabbllee 11.. A selection of ongoing clinical trials determining metformin’s effect on oncologic diseases TTyyppee ooff ccaanncceerrOOffffiicciiaall ttiittlleeTTrriiaall iiddeennttiiffiieerr nnooEEssttiimmaatteedd PPuurrppoossee ooff tthhee ssttuuddyy eennrroollllmmeenntt prostate cancerMetformin in Castration-Resistant Prostate CancerNCT01215032106prospective study to evaluate metformin’s effect on PSA concentration in prostate cancer patients receiving androgen deprivation therapy pancreatic cancerCombination Chemotherapy With or Without NCT0116773882randomized phase II trial Metformin Hydrochloride in Treating Patients Withto evaluate the effectiveness of combination chemotherapy with Metastatic Pancreatic Canceror without metformin hydrochloride in treating patients with metastatic pancreatic cancer endometrial cancerMetformin and Endometrial CancerNCT0120567230non-randomized phase I trial to evaluate the effect of metformin on s6K expression in endometrial cancer colorectal cancerA Trial of Metformin for Colorectal Cancer RiskNCT0131246739a phase II study Reduction Among Patients With a Historyto evaluate the potential preventive effect of metformin in patients of Colorectal Adenomas and Elevated Body with history of colorectal adenomas and a BMI > 30 Mass Index breast cancerA Phase III Randomized Trial of Metformin vs PlaceboNCT011014383582a phase III study in Early Stage Breast Cancer A Phase III Randomizedto evaluate the effect of the addition of metformin to standard Trial of Metformin vs Placebo in Early Stage Breast Cancerchemotherapy in women with early-stage breast cancer. breast cancerMetformin Hydrochloride in Treating Women With Stage INCT0098449030a phase II study or Stage II Breast Cancer That Can Be Removed By Surgeryto evaluate the effect of metformin on cell proliferation (Ki67) and apoptosis (kaspaza 3) in women with stage I or stage II cancer breast cancerMetformin Pre-Surgical Pilot StudyNCT0093057935a phase II study to evaluate the effect of metformin on the AMPK/mTOR pathway in women with newly diagnosed early-stage breast cancer. breast cancerThe Impact of Obesity and Obesity TreatmentsNCT0093330924phase I study on Breast Cancerto evaluate the effect of aromatase inhibitor treatment in combination with metformin and rosiglitazone in obese women with estrogen receptor positive breast cancer breast cancerClinical and Biologic Effects of Metformin in Early StageNCT0089788440to evaluate the effect of pre-operative metformin therapy on cell Breast Cancerproliferation in tumor tissue in women diagnosed with breast cancer breast cancerA Trial of Standard Chemotherapy With Metformin (vs Placebo)NCT0131023178randomized phase II trial in Women With Metastatic Breast Cancerto evaluate standard chemotherapy with metformin on PFS in women with metastatic breast cancer. breast cancerEffect of Metformin on Breast Cancer MetabolismNCT0126648640to measure metformin induced effects in phosphorylation of S6K, 4E-BP-1 and AMPK breast cancerThe Use of Metformin in Early Breast Cancer PatientsNCT0130200230to evaluate the effects of metformin on proliferation (Ki67) and apoptosis Pre-Surgery(TUNEL) in women with stage I or II breast cancer
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Address for correspondence M
Moonniikkaa PPaawwaałłoowwsskkaa Department of Oncology
Poznan University of Medical Sciences Szamarzewskiego 82/84
60-569 Poznań, Poland tel. +48 61 854 90 20
Submitted: 13.08.2011 Accepted: 2.04.2012
